The present invention concerns novel IL-5 inhibiting 6-azauracil derivatives useful for treating eosinophil-dependent inflammatory diseases; to processes for their preparation and compositions comprising them. It further relates to their use as a medicine.
Eosinophil influx, leading to subsequent tissue damage, is an important pathogenic event in bronchial asthma and allergic diseases. The cytokine interleukin-5 (IL-5), produced mainly by T lymphocytes as a glycoprotein, induces the differentiation of eosinophils in bone marrow and, primes eosinophils for activation in peripheral blood and sustains their survival in tissues. As such, IL-5 plays a critical role in the process of eosinophilic inflammation. Hence, the possibility that inhibitors of IL-5 production would reduce the production, activation and/or survival of eosinophils provides a therapeutic approach to the treatment of bronchial asthma and allergic diseases such as, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and also other eosinophil-dependent inflammatory diseases.
Steroids, which strongly inhibit IL-5 production in vitro, have long been used as the only drugs with remarkable efficacy for bronchial asthma and atopic dermatitis, but they cause various serious adverse reactions such as diabetes, hypertension and cataracts. Therefore, it would be desirable to find non-steroidal compounds having the ability to inhibit IL-5 production in human T-cells and which have little or no adverse reactions.
U.S. Pat. No. 4,631,278 discloses xcex1-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitriles and U.S. Pat. No. 4,767,760 discloses 2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones, all having anti-protozoal activity, in particular, anti-coccidial activity. EP 831,088 discloses 1,2,4-triazine-3,5-diones as anticoccidial agents.
The present invention provides compounds which have never been described hitherto and which possess a remarkable pharmacological activity as inhibitors of the production of IL-5.
The present invention is concerned with the compounds of formula 
the N-oxides, the pharmaceutically acceptable addition salts, quaternary amines and the stereochemically isomeric forms thereof, wherein
p represents an integer being 0, 1, 2, 3 or 4;
q represents an integer being 0, 1, 2, 3, 4 or 5;
X represents O, S, NR3 or a direct bond; or
xe2x80x94Xxe2x80x94R2 taken together may represent cyano;
R1 represents hydrogen, hydroxy, halo, amino, mono- or di(C1-4alkyl)amino, C1-6alkyl, C1-6alkyloxy, C3-7cycloalkyl, aryl, arylC1-6alkyl, aminoC1-4alkyl, mono- or di(C1-4alkyl)aminoC1-4alkyl or mono- or di(C1-4alkyl)amino-C1-4alkylamino;
R2 represents aryl, Het1, C3-7cycloalkyl optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-6alkyl or C1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C1-4alkyl)amino, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-6alkyloxy optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-6alkylsulfonyloxy, C3-7cycloalkyl optionally substituted with xe2x80x94Cxe2x95x90O)xe2x80x94Zxe2x80x94R14, aryl, aryloxy, arylthio, Het1, Het1oxy and Het1thio; and if X is O, S or NR3, then R2 may also represent xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, aminothiocarbonyl, C1-4alkylcarbonyl optionally substituted with xe2x80x94C(xe2x95x90Q)xe2x80x94Zxe2x80x94R14, C1-4alkylthiocarbonyl optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, arylcarbonyl, arylthiocarbonyl, Het1carbonyl or Het1thiocarbonyl;
R3 represents hydrogen or C1-4alkyl;
each R4 independently represents xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, C1-6alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6, NR7R8 or C1-4alkyl substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, Het3, R6 or NR7R8;
each R5 independently represents xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, C1-6alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6, NR7R8 or C1-4alkyl substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, Het3, R6 or NR7R8;
each R6 independently represents C1-6alkylsulfonyl, aminosulfonyl, mono- or di-(C1-4alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhaloC1-6alkyl-sulfonyl, C1-6alkylsulfonyl, phenylC1-4alkylsulfonyl, piperazinylsulfonyl, piperidinyl-sulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-C1-4alkyl-N-piperidinylaminosulfonyl or mono- or di(C1-4alkyl)aminoC1-4alkylsulfonyl;
each R7 and each R8 are independently selected from hydrogen, C14alkyl, hydroxy-C1-4alkyl, dihydroxyC1-4alkyl, aryl, arylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyl-carbonyl, arylcarbonyl, Het3carbonyl, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, mono- or di(C1-4alkyl)amino-C)4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3amino-thiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, Het3 and R6; or R7 and R8 taken together with the nitrogen atom to which they are attached form a radical of formula 
R9 and R10 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyl-carbonyl, phenylcarbonyl, Het3carbonyl, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, mono- or di(C1-4alkyl)amino-C1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het3 aminocarbonyl, Het3 aminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, Het3 and R6; or R9 and R10 taken together with the nitrogen atom to which they are attached form a radical of formula 
each R11 independently being selected from hydroxy, mercapto, cyano, nitro, halo, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, trihalomethyl, C1-4alkyloxy optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, formyl, trihaloC1-4alkylsulfonyloxy, R6, NR7R8, C(xe2x95x90O)NR15 R16, aryl, aryloxy, arylcarbonyl, C3-7cycloalkyl optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C3-7cycloalkyloxy optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, phthalimide-2-yl, Het3, Het4 and C(xe2x95x90O)Het3;
R12 and R13 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyl-carbonyl, phenylcarbonyl, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, mono- or di(C1-4alkyl)aminoC1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94R14 and R6; or R9 and R10 taken together with the nitrogen atom to which they are attached form a radical of formula 
xe2x80x83each Z independently represents O, S, NH, xe2x80x94CH2xe2x80x94Oxe2x80x94 xe2x80x94CH2xe2x80x94Sxe2x80x94 whereby xe2x80x94CH2xe2x80x94 is attached to the carbonyl group;
each R14 independently represents hydrogen, C1-20acyl (having a straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms), C1-20alkyl, C3-20alkenyl optionally substituted with phenyl, C3-20alkynyl, C3-7cycloalkyl, polyhaloC1-20alkyl, Het5, phenyl or C1-20alkyl substituted with one or more substituents selected from hydroxy, NR17, R18, phenyl, mono- or di(C1-4alkyl)amino, cyano, Het5, C1-4alkyloxycarbonyl, phenylC1-4alkyloxycarbonyl and C3-7cycloalkyl; or R14 represents a radical of formula 
wherein n is 0 to 5; m is 1 to 4; s is zero to 4; r is 0 to 2;
Ra, Rb, Rc, Rd, Re and Rf are each independently hydrogen, or C1-6alkyl; phenyl or C3-7cycloalkyl; or
Re and Rf taken together may form xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x94CH2xe2x80x94CH2xe2x80x94;
Rg, Rh and Rk are each independently hydrogen or C1-4alkyl;
each Rj independently is C1-4alkyl;
Ri is xe2x80x94Oxe2x80x94R6, C1-6alkyl, phenyl or C3-7cycloalkyl optionally substituted with C1-4alkyloxy;
Rn is hydrogen, C1-4alkyl, phenyl, phenylC1-4alkyl or C3-7cycloalkyl;
Rm is hydrogen or C1-4alkyloxy; or
xe2x80x94Zxe2x80x94R14 taken together form a radical of formula 
R15 and R16 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, aryl, arylC1-4alkyl, C1-4alkyloxyC1-4alkyl, xe2x80x94C(xe2x95x90O)Zxe2x80x94R14, arylcarbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, arylaminocarbonyl, arylamino-10 thiocarbonyl, aminocarbonylmethylene, mono- or di(C1-4alkyl)aminocarbonyl-methylene, Het3aminocarbonyl, Het3aminothiocarbonyl, pyridinylC1-4alkyl, Het3 or R6; or R15 and R16 taken together with the nitrogen atom to which they are attached form a radical of formula 
R17 and R18 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4akyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyl-carbonyl, phenylcarbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, phenylamino-carbonyl, phenylaminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94C1-6alkyl, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94C1-6alkyl, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94C1-6alkyl and R6;
aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C1-4alkyl, C3-7cycloalkyl, C1-4alkyloxy, formyl, polyhaloC1-4alkyl, NR9R10, xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, R6, xe2x80x94Oxe2x80x94R6; phenyl, Het3, C(xe2x95x90O)Het3, and C1-4alkyl substituted with one or more substituents each independently selected from halo, hydroxy,
C1-4alkyloxy, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, Het3 or NR9R10;
Het1 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl, imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with one or two substituents independently selected from Het2 and R11;
Het2 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R11 and C1-4alkyl optionally substituted with one or two substituents each independently selected from R11;
Het3 represents a monocyclic heterocycle selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C1-4alkyl, C1-4alkyloxy, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-4alkylcarbonyl, phenylC1-4alkyl, piperidinyl, NR12R13, R6 and C1-4alkyl substituted with one or two substituents each independently selected from hydroxy, C1-4alkyloxy, phenyl, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R4, R6or NR12R13;
Het4 represents a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl;
Het5 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzo-thienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimida-zolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two, three or four substituents each independently selected from hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, piperidinyl, NR17R18, C(xe2x95x90O)xe2x80x94Zxe2x80x94C1-6alkyl, R6, sulfonamido and C1-4alkyl substituted with one or two substituents independently selected from hydroxy, C1-4alkyloxy, phenyl, C(xe2x95x90O)xe2x80x94Zxe2x80x94C1-6alkyl, xe2x80x94Yxe2x80x94C1-6alkanediylxe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94C1-6alkyl, R6 and NR17R18;
provided however that
R2 is other than aminocarbonyl, C1-6alkyloxycarbonylC1-6alkyl; and
R11 is other than carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl, C1-4alkylaminocarbonyl, hydroxyC1-4alkylaminocarbonyl, C1-4alkylcarbonylaminocarbonyl, C3-7cycloalkylaminocarbonyl; and
R7, R8, R9, R10, R12, R13, R15 and R16 are other than C1-4alkylcarbonyloxyC1-4alkylcarbonyl, hydroxyC1-4alkylcarbonyl; and
Het3 is other than a monocyclic heterocycle substituted with carboxyl or C1-4alkyloxycarbonyl; and
the compounds of formula (I) contain at least one xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14 moiety.
A special group of compounds are those compounds of formula (I) wherein
R represents aryl, Het1, C3-7cycloalkyl optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-6alkyl or C1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C1-4alkyl)amino, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-6alkyloxy optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-6alkylsulfonyloxy, C3-7cycloalkyl optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, aryl, aryloxy, arylthio, Het1, Het1oxy and Het1thio; and if X is O, S or NR3, then R2 may also represent xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, aminothiocarbonyl, C1-4alkylcarbonyl optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-4alkylthiocarbonyl optionally: substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, arylcarbonyl, arylthiocarbonyl;
each R6 independently represents C1-6alkylsulfonyl, aminosulfonyl, mono- or di(C1-4alkyl)aminosulfonyl, mono or di(benzyl)aminosulfonyl, polyhaloC1-6alkylsulfonyl, C1-6alkylsulfonyl, phenylC1-4alkylsulfonyl, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-C1-4alkyl-N-piperidinylaminosulfonyl;
each R7 and each R8 are independently selected from hydrogen, C1-4alkyl, hydroxy-C1-4alkyl, dihydroxyC1-4alkyl, aryl, arylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyl-carbonyl, arylcarbonyl, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, mono- or di(C1-4alkyl)aminoC1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, Het3 and R6;
R9 and R10 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyl-carbonyl, phenylcarbonyl, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, mono- or di(C1-4alkyl)aminoC1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, Het3 and R6;
each R11 independently being selected from hydroxy, mercapto, cyano, nitro, halo, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, trihalomethyl, C1-4alkyloxy optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, formyl, trihaloC1-4alkylsulfonyloxy, R6, NR7R8, C(xe2x95x90O)NR15R16, aryl, aryloxy, arylcarbonyl, C3-7cycloalkyl optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C3-7cycloalkyloxy optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, phthalimide-2-yl, Het3 and C(xe2x95x90O)Het3;
R12 and R13 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyl-carbonyl, phenylcarbonyl, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, mono- or di(C1-4alkyl)aminoC1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl and R6;
each R14 independently represents hydrogen, C1-20acyl (having a straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms), C1-20alkyl, C3-7cycloalkyl, polyhaloC1-20alkyl; or R14 represents a radical of formula 
Ra, Rb, Rc, Rd, Re and Rf are each independently hydrogen, C1-6alkyl or C3-7cycloalkyl; or
Re and Rf taken together may form xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94;
R15 and R16 are each independently selected from dihydroxyC1-4alkyl, aryl, arylC1-4alkyl, C1-4alkyloxyC1-4alkyl, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, arylcarbonyl, mono- or di(C1-4alkyl)-aminoC1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, pyridinylC1-4alkyl, Het3 or R6;
aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, halo, hydroxy, C1-4alkyl, C1-4alkyloxy, polyhaloC1-4alkyl, NR9R10, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, R6, phenyl, Het3, and C1-4alkyl substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14 or NR9R10;
Het1 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyrdazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl, imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with Het2 and R11;
Het2 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanyl,dithianyl, trithianyl, triazinyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R11 and C1-4alkyl optionally substituted with R11;
Het3 represents a monocyclic heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two, substituents each independently selected from C1-4alkyl, C1-4alkyloxy, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-4alkylcarbonyl, phenylC1-4alkyl, piperidinyl, NR12R13, R6 and C1-4alkyl substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, R6 or NR12R13.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like C1-20alkyl is meant to include C1-6alkyl and the higher homologues thereof having 7 to 20 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl, nonadecyl, eicosyl and the like C5-20alkyl is meant to include C1-20alkyl except for C1-4alkyl; polyhaloC1-4alkyl is defined as polyhalosubstituted C1-4alkyl, in particular C1-4alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl; polyhaloC1-6alkyl is defined as polyhalosubstituted C1-6alkyl; polyhaloC1-20alkyl is defined as polyhalosubstituted C1-20alkyl. The term C1-4alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C2-6alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 2 to 6 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like. The term C3-20alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 20 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like; and the carbon of said C3-20alkenyl connected to the remainder of the molecule preferably is saturated; and the term C3-20alkynyl defines straight and branched chain hydrocarbon radicals containing one triple bond and having from 3 to 20 carbon atoms such as, for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl and the like; and the carbon of said C3-20alkynyl connected to the remainder of the molecule preferably is saturated.
Het1, Het2, Het3, Het4 and Het5 are meant to include all the possible isomeric forms of the heterocycles mentioned in the definition of Het1, Het2, Het3, Het4 or Het5, for instance, pyrrolyl also includes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyl and 1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl; thiadiazolyl includes 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl.
The heterocycles represented by Het1, Het2, Het3, Het4 and Het5 may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heterocycle is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is thiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when it is benzthiazolyl, it may be 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl.
The C1-20acyl is derived from
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxy-acetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulphonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine, choline and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. For example, one or more nitrogen atoms of any of the heterocycles in the definition of Het1, Het2, Het3, Het4 and Het5 may be N-oxidised.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For example, a hydroxy substituted triazine moiety may also exist as the corresponding triazinone moiety; a hydroxy substituted pyrimidine moiety may also exist as the corresponding pyrimidinone moiety.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible stereoisomeric forms in which the compounds of formula (I) can exist. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centres may have the R- or S-configuration, used herein in accordance with Chemical Abstracts nomenclature. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The compounds of formula (I) and some of the intermediates in the present invention contain one or more asymmetric carbon atoms. The pure and mixed stereochemically isomeric forms of the comppounds of formula (I) are intended to be embraced within the scope of the present invention.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to also include their N-oxide forms, their pharmaceutically acceptable addition salts, quaternary amines and their stereochemically isomeric forms.
The numbering of the phenyl ring bearing substituent R4 is given hereinbelow and is used herein as such when indicating the position of the R4 substituents on said phenyl ring, unless otherwise indicated. 
The carbon atom bearing the two phenyl rings and the R1 and xe2x80x94Xxe2x80x94R2 substituents will be referred herein as the central carbon atom.
An interesting group of compounds are those compounds of formula (I) wherein the 6-azauracil moiety is connected to the phenyl ring in the para or meta position relative to the central carbon atom; preferably in the para position.
Another interesting group contains those compounds of formula (I) wherein one or more of the following restrictions apply:
p is 0, 1 or 2;
X is S, NR3, or a direct bond; more in particular NH or a direct bond;
each R5 independently is halo, polyhaloC1-6alkyl, C1-6alkyl, C1-6alkyloxy or aryl, preferably, chloro or trifluoromethyl, more preferably chloro;
the at least one xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14 moiety contained by the compound of formula (I) is born by R2;
R2 is Het1 or C1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C1-4alkyl)amino, C(xe2x95x90O)xe2x80x94Zxe2x80x94R14 C1-6alkyloxy optionally substituted with C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-6alkylsulfonyloxy, C3-7cycloalkyl optionally substituted with C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, aryl, aryloxy, arylthio, Het1, Het1oxy and Het1thio; and if X is O, S or NR , then R2 may also represent aminothiocarbonyl, C1-4alkylcarbonyl optionally substituted with C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-4alkylthiocarbonyl optionally substituted with C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, arylcarbonyl, arylthiocarbonyl, Het1carbonyl or Het1thiocarbonyl; particularly R2 is Het1 or in the event X is NH, R2 may also be aminothiocarbonyl or Het1carbonyl;
R1 is hydrogen or methyl; preferably, methyl;
R6 is C1-6alkylsulfonyl or aminosulfonyl;
R7 and R8 are each independently hydrogen, C1-4alkyl, Het3 or R6;
R9 and R10 are each independently hydrogen, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, aminocarbonyl, Het3carbonyl, Het3 or R6;
R11 is cyano, nitro halo, C1-4alkyloxy, formyl, NR7R8, C(xe2x95x90O)NR15R16, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, aryl, arylcarbonyl, Het3, Het4 or C(xe2x95x90O)Het3; more preferably R11 is phenyl, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94R14, or, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94R14;
R14 is dihydrofuranyl, C5-20alkyl, C3-20alkenyl, polyhaloC1-6alkyl, Het5 or C1-20alkyl substituted with one or more substituents selected from phenyl, C1-4alkylamino, cyano, Het1, hydroxy and C3-7cycloalkyl;
R17 and R18 are each independently hydrogen or phenyl;
aryl is phenyl optionally substituted with one, two or three substituents each independently selected from nitro, cyano, halo, hydroxy, C1-4alkyl, C3-7cycloalkyl, C1-4alkyloxy, formyl, polyhaloC1-4alkyl, NR9R10, C(xe2x95x90O)NR9R10, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Oxe2x80x94R6, phenyl, C(xe2x95x90O)Het3 and C1-4alkyl substituted with one or more substituents each independently selected from halo, hydroxy, C1-4alkyloxy, C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, Het3 or NR9R10;
Het1 is a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, in particular imidazolyl, oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4akyl optionally substituted with Het2 or R11; preferably Het1 is imidazolyl, oxadiazolyl, thiazolyl or pyridinyl each independently and optionally substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with Het2 or R11;
Het2 is an aromatic heterocycle; more in particular furanyl, thienyl, pyridinyl or benzothienyl, wherein said aromatic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R11 and C1-4alkyl; :
Het3 is azetidinyl, piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl each independently and optionally substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C1-4alkyl, C1-4alkylcarbonyl, piperidinyl and C1-4alkyl substituted with one or two substituents independently selected from hydroxy, C1-4alkyloxy and phenyl;
Het4 is thienyl;
Het5 is piperidinyl or piperazinyl optionally substituted with C1-4alkyl or sulfonamido.
Suitably, Het1 represents a heterocycle selected from imidazolyl, triazolyl, furanyl, oxazolyl, thiazolyl, thiazolinyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, benzothiazolyl, benzoxazolyl, purinyl, 1H-pyrazolo-[3,4-d]pyrimidinyl, benzimidazolyl, thiazolopyridinyl, oxazolopyridinyl, imidazo-[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with Het2 or R11. Suitably, Het2 represents furanyl, thienyl or pyridinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with C1-4alkyl. Suitably, Het3 represents pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two or three substituents each independently selected from C1-4alkyl, C1-4alkyloxy, xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, C1-4alkylcarbonyl, phenylC1-4alkyl, piperidinyl, NR12R13 and C1-4alkyl substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14 or NR12R13.
Particular compounds are those compounds of formula (I) wherein R4 and R5 each independently are xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, halo, polyhaloC1-6alkyl, C1-6alkyl optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Z7R14, C1-6alkyloxy or aryl, more in particular, chloro or trifluoromethyl.
Other particular compounds are those compounds of formula (I) wherein R2 represents aryl, Het1, C3-7cycloalkyl optionally substituted with xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14 or C1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxy, C1-6alkylsulfonyloxy, C1-6alkyloxycarbonyl, C3-7cycloalkyl, aryl, aryloxy, arylthio, Het1, Het1oxy and Het1thio; and if X is O, S or NR3, then R2 may also represent xe2x80x94C(xe2x95x90O)xe2x80x94Zxe2x80x94R14, aminothiocarbonyl, CC1-4alkylcarbonyl, C1-4alkylthiocarbonyl, arylcarbonyl or arylthiocarbonyl; more in particular R2 is oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with Het2 or R11.
Yet other particular compounds are those compounds of formula (I) wherein X is O, S, NH or a direct bond, more preferably S or a direct bond, most preferably a direct bond.
Preferred compounds are those compounds of formula (I) wherein q is 1 or 2 and one R4 substituent, preferably chloro, is in the 4 position.
Other preferred compounds are those compounds of formula (I) wherein p is 1 or 2 and the one or two R5 substituents, preferably chloro, are in the ortho position relative to the central carbon atom.
In order to simplify the structural representation of the compounds of formula (I), the group 
will hereinafter be represented by the symbol D.
Compounds of formula (I) can generally be prepared by reacting an intermediate of formula (I) wherein W1 is a suitable leaving group such as, for example, a halogen atom, with an appropriate reagent of formula (III). 
Said reaction may be performed in a reaction-inert solvent such as, for example, acetonitrile, N,N-dimethylformamide, acetic acid, tetrahydrofuran, ethanol or a mixture thereof. Alternatively, in case the reagent of formula (III) acts as a solvent, no additional reaction-inert solvent is required. The reaction is optionally carried out in the presence of a base such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium bicarbonate, sodiumethanolate and the like. Convenient reaction temperatures range between xe2x88x9270xc2x0 C. and reflux temperature.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallisation, distillation, trituration and chromatography.
Alternatively, compounds of formula (I) may generally be prepared by cyclising an intermediate of formula (IV) wherein L is a suitable leaving group such as, for example, C1-6alkyloxy or halo, and E represents an appropriate electron attracting group such as, for example, an ester, an amide, a cyanide, C1-6alkylsulfonyloxy and the like groups; and eliminating the group E of the thus obtained triazinedione of formula (V). Said reaction procedure is analogous to the one described in EP-A-0,170,316. 
Some of the compounds and intermediates of the present invention can be prepared according to or analogous to the procedures described in EP-A-0,170,316 and EP-A-0,232,932.
For instance, scheme 1 depicts a reaction pathway for the preparation of compounds of formula (I) wherein R1 is hydrogen and X is a direct bond, said compounds being represented by formula (I-a-1). A ketone of formula (VI) can be reacted with a reagent of formula (VII) wherein W2 is a suitable leaving group such as, for example, a halogen, in a reaction-inert solvent such as, for example, tetrahydrofuran, diethylether, and in the presence of a suitable base such as, for example, butyl lithium, thus forming an intermediate of formula (VIII). The hydroxy group of the intermediates of formula (VIII) may be eliminated by using a suitable reagent such as for example, formamide in acetic acid or triethylsilane in trifluoroacetic acid, thus obtaining an intermediate of formula (IX) of which the nitro group may subsequently be reduced to an amino group which in turn may then be converted to the 6-azauracil group as described in EP-A-0,170,316, thus obtaining compounds of formula (I-a-1). 
In addition to the reaction procedure shown in scheme 1, other compounds of formula (I) wherein X is a direct bond may be prepared starting from a ketone of formula (X) (Scheme 2). Reacting said ketone of formula (X) with an intermediate of formula (III) wherein X is a direct bond, said intermediates being represented by formula (III-a), results in a compound of formula (I) wherein R1 is hydroxy and X is a direct bond, said compounds being represented by formula (I-a-2). Said reaction may be performed in a reaction-inert solvent such as, for example, tetrahydrofuran, diethylether, diisopropyl-acetamide or a mixture thereof, in the presence of a base such as, for example, butyl lithium. Alternatively, intermediate of formula (III-a) may first be transformed into a Grignard reagent, which may then be reacted with the ketone of formula (X). Said compounds of formula (I-a-2) may further be converted to compounds of formula (I) wherein R1 is a C1-6alkyloxy group represented by formula (I-a-3) using art-known group transformation reactions. The compounds of formula (I-a-2) may also be converted to compounds of formula (I) wherein R1 is halo, said compounds being represented by formula (I-a-4). A convenient procedure is converting the hydroxy group to a chlorine atom using a suitable reagent such as, for example, thionyl chloride. Said compounds of formula (I-a4) may further be converted to compounds of formula (I) wherein R1 is amino, said compounds being represented by formula (I-a-5), using ammonia or a functional derivative thereof, in a reaction-inert solvent such as, for example, tetrahydrofuran; or may be converted to compounds of formula (I-a-3) using art-known group transformation reactions.
Reducing the ketone of formula (X) to its corresponding hydroxy derivative of formula (XI) using a suitable reducing agent such as, for example, sodiumborohydride in a reaction-inert solvent such as for example, water, an alcohol, tetrahydrofuran or a mixture thereof; subsequently converting said hydroxy group to a suitable leaving group W4 being for example a halogen, thus obtaining an intermediate of formula (XII), and finally reacting said intermediate of formula (XII) with an intermediate of formula (III) in a suitable solvent such as, for example, tetrahydrofuran, N,N-dimethyl-formamide, acetonitrile, acetic acid, ethanol or a mixture thereof, and optionally in the presence of a suitable base such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene or sodiumbicarbonate, will result in a compound of formula (I) wherein R1 is hydrogen, said compounds being represented by formula (I-b).
Alternatively, intermediates of formula (XI) can be directly transformed to compounds of formula (I-b) wherein X is S, said compounds being represented by formula (I-b-1), using a suitable mercapto containing reagent of formula R2xe2x80x94SH in a suitable reaction solvent such as, for example, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or the like.
Also starting from a ketone of formula (X), compounds of formula (I) may be prepared wherein R1 is hydrogen and xe2x80x94Xxe2x80x94R2 is xe2x80x94NHxe2x80x94C(xe2x95x90O)-(aryl or C1-6alkyl), said compounds being represented by formula (I-c). To that effect, a ketone of formula (X) is reacted with formamide in formic acid or a functional derivative thereof, at elevated temperatures. The resulting intermediate of formula (XII) is hydrolysed to the corresponding amine of formula (XIV), which may then be further reacted with an intermediate of formula (XV) wherein W3 is a suitable leaving group, in the presence of a suitable base, such as, for example pyridine, optionally in the presence of a reaction-inert solvent such as, for example, dichloromethane. 
Compounds of formula (I) wherein X is a direct bond and R2 is a heterocycle, said compounds being generally represented by formula (I-d), can conveniently be prepared by cyclisation of the appropriate intermediate. Intramolecular cyclisation procedures are feasible and scheme 3 lists several examples.
Starting point is the conversion of the cyano group of a compound of formula (I) wherein xe2x80x94Xxe2x80x94R2 is cyano, said compounds being represented by formula (I-e), to a carboxyl group thus forming intermediates of formula (XVII) using art-known techniques such as, for example, using a combination of sulphuric and acetic acid in water, which in turn may be further reacted to acyl halides of formula (XVIII), for instance, the acyl chloride derivative may be prepared using thionyl chloride. 
The intermediate of formula (XVIII) may be reacted with an intermediate of formula (XIX-a) wherein Y is O, S or NR3, to form an intermediate of formula (XX) in the presence of a base such as, for example, pyridine. Said intermediate of formula (XX) may further be cyclised to a compound of formula (I) wherein xe2x80x94Xxe2x80x94R2 is an optionally substituted benzothiazole or benzoxazole, said compounds being represented by formula (I-d-1), in the presence of a suitable solvent such as, for example, acetic acid, at an elevated temperature, preferably at reflux temperature. It may be convenient to prepare compounds of formula (I-d-1) without isolating intermediates of formula (XX). Analogously, an intermediate of formula (XVIII) may be reacted with an intermediate of formula (XIX-b) to form an intermediate of formula (XXI) which is cyclised to a compound of formula (I) wherein xe2x80x94Xxe2x80x94R2 is an optionally 3-substituted 1,2,4-oxadiazole, said compounds being represented by formula (I-d-2), in a reaction-inert solvent such as, for example, toluene, at an elevated temperature, preferably at reflux temperature. Also analogously, an intermediate of formula (XVI) may be reacted with an intermediate of formula (XIX-c) wherein Y is O, S or NR3, to form an intermediate of formula (XXII) which is cyclised to a compound of formula (I) wherein xe2x80x94Xxe2x80x94R2 is an optionally substituted 1,2,4-triazole, 1,3,4-thiadiazole or 1,3,4-oxadiazole, said compounds being represented by formula (I-d-3), in a suitable solvent such as, for example, phosphorus oxychloride.
Also analogously, an intermediate of formula (XVIII) may be reacted with an intermediate of formula (XIX-d) wherein Y is O, S or NR3, to form an intermediate of formula (XXIII) which is cyclised to a compound of formula (I) wherein xe2x80x94Xxe2x80x94R2 is an optionally amino substituted 1,2,4-triazole, 1,3,4-thiadiazole or 1,3,4-oxadiazole, said compounds being represented by formula (I-d4) in a reaction-inert solvent such as, for example, toluene, and in the presence of an acid; or, which is cyclised to a compound of formula (I) wherein xe2x80x94Xxe2x80x94R2 is a disubstituted 1,3,4-triazole, said compounds being represented by formula (I-d-5).
The nitrile derivative of formula (XVI) may also be reacted with hydroxylamine hydrochloride or a functional derivative thereof, thus forming an intermediate of formula (XXIV) which may be reacted with an intermediate of formula (XXV) to form a compound of formula (I) wherein xe2x80x94Xxe2x80x94R2 is an optionally 5-substituted 1,2,4-triazole, 1,2,4-thiadiazole or 1,2,4-oxadiazole, said compounds being represented by formula (I-d-6), in a reaction-inert solvent such as, for example, methanol, butanol or a mixture thereof, and in the presence of a base such as, for example, sodium methanolate.
Compounds of formula (I-d) wherein the heterocycle is substituted 2-thiazolyl, said compounds being represented by formula (I-d-7), can be prepared by reacting an intermediate of formula (XVI) with hydrogensulfide or a functional derivative thereof, in a reaction inert solvent such as, for example, pyridine, optionally in the presence of a suitable base such as, for example, triethylamine, thus forming an intermediate of formula (XXVI), which may subsequently be reacted with an intermediate of formula (XXVII) or a functional derivative thereof such as the ketal derivative thereof, in a reaction-inert solvent such as for example, ethanol, and optionally in the presence of an acid such as, for example, hydrogenchloride. 
Compounds of formula (I-d) wherein the heterocycle is substituted 5-thiazolyl and R1 is hydrogen, said compounds being represented by formula (I-d-8), can be prepared following the reaction procedure depicted in scheme 4. 
Initially, an intermediate of formula (XXVIII) wherein P is a protective group such as, for example, a C1-6alkylcarbonyl group, is reacted with a thiazole derivative of formula (XXIX) in the presence of a suitable base such as, for example, butyl lithium, in a reaction inert solvent such as, for example, tetrahydrofuran, thus forming an intermediate of formula (XXX). It may be convenient to perform said reaction under an inert atmosphere at lower temperature, preferably at about xe2x88x9270xc2x0 C. The hydroxy group and the protective group P of said intermediates (XXX) may be removed using art-known procedures such as, for example, stannous chloride and hydrochloric acid in acetic acid, thus forming an intermediate of formula (XXXI), of which the amino group may further be converted to a 6-azauracil moiety according to the procedure described in EP-A-0,170,316, thus forming a compound of formula (I-d-8).
Also, compounds of formula (I-d) wherein the heterocycle is 4-thiazolyl, said compounds being represented by formula (I-d-9), can be prepared following the reaction procedure depicted in scheme 5. 
An intermediate of formula (XVIII) is reacted with a Grignard reagent of formula RCH2MgBr or a functional derivative thereof to form an intermediate of formula (XXXII), which may be halogenated, preferably brominated, in the a-position using a suitable reagent such as trimethylphenylammonium tribromide in tetrahydrofuran, thus forming an intermediate of formula (XXXII). Said intermediate (XXXI) may then be reacted with a thioamide of formula (XXXIV) to form a compound of formula (I-d9), in a reaction-inert solvent such as, for example, ethanol, at an elevated temperature, preferably reflux temperature.
The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation of which some examples are. mentioned hereinabove.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter-current distribution, liquid chromatography and the like.
Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallisation or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallisation or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
Some of the intermediates and starting materials as used in the reaction procedures mentioned hereinabove are known compounds and may be commercially available or may be prepared according to art-known procedures.
IL-5, also known as eosinophil differentiating factor (EDF) or eosinophil colony stimulating factor (Eo-CSF), is a major survival and differentiation factor for eosinophils and therefore thought to be a key player in eosinophil infiltration into tissues. There is ample evidence that eosinophil influx is an important pathogenic event in bronchial asthma and allergic diseases such as, cheilitis, irritable bowel disease, eczema, urticaria, vasculitis, vulvitis, winterfeet, atopic dermatitis, pollinosis, allergic rhinitis and allergic conjunctivitis; and other inflammatory diseases, such as eosinophilic syndrome, allergic angiitis, eosinophilic fasciitis, eosinophilic pneumonia, PIE syndrome, idiopathic eosinophilia, eosinophilic myalgia, Crohn""s disease, ulcerative colitis and the like diseases.
The present compounds also inhibit the production of other chemokines such as monocyte chemotactic protein-1 and -3 (MCP-1 and MCP-3). MCP-1 is known to attract both T-cells, in which IL-5 production mainly occurs, and monocytes, which are known to act synergetically with eosinophils (Carr et al., 1994, Immunology, 91, 3652-3656). MCP-3 also plays a primary role in allergic inflammation as it is known to mobilize and activate basophil and eosinophil leukocytes (Baggiolini et al., 1994, Immunology Today, 15(3), 127-133).
The present compounds have no or little effect on the production of other chemokines such as IL-1, IL-2, IL-3, IL-4, IL-6, IL-10, xcex3-interferon (IFN-xcex3) and granulocyte-macrophage colony stimulating factor (GM-CSF) indicating that the present IL-5 inhibitors do not act as broad-spectrum immunosuppressives.
The selective chemokine inhibitory effect of the present compounds can be demonstrated by in vitro chemokine measurements in human blood. In vivo observations such as the inhibition of eosinophilia in mouse ear, the inhibition of blood eosinophilia in the Ascaris mouse model; the reduction of serum IL-5 protein production and splenic IL-5 mRNA expression induced by anti-CD3 antibody in mice and the inhibition of allergen- or Sephadex-induced pulmonary influx of eosinophils in guinea-pig are indicative for the usefulness of the present compounds in the treatment of eosinophil-dependent inflammatory diseases.
The present inhibitors of IL-5 production are particularly useful for administration via inhalation.
The intermediates of formula (XI-a) are interesting intermediates. Not only have they a particular usefulness as intermediates in the preparation of the compounds of formula (I), they also have valuable pharmacological activity.
In view of the above pharmacological properties, the compounds of formula (I) can be used as a medicine. In particular, the present compounds can be used in the manufacture of a medicament for treating eosinophil-dependent inflammatory diseases as mentioned hereinabove, more in particular bronchial asthma, atopic dertmatitis, allergic rhinitis and allergic conjunctivitis.
In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from eosinophil-dependent inflammatory diseases, in particular bronchial asthma, atopic dertmatitis, allergic rhinitis and allergic conjunctivitis. Said method comprises the systemic or topical administration of an effective amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.
The present invention also provides compositions for treating eosinophil-dependent inflammatory diseases comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as parenteral administration; or topical administration such as via inhalation, a nose spray or the like. Application of said compositions may be by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclo-dextrins or their derivatives. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility.
Appropriate cyclodextrins are xcex1-, xcex2-, xcex3-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclo-dextrin are substituted with C1-6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated xcex2-CD; hydroxyC1-6alkyl, particularly hydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyC1-6alkyl, particularly carboxymethyl or carboxy-ethyl; C1-6alkylcarbonyl, particularly acetyl; C1-6alkyloxycarbonylC1-6alkyl or carboxy-C1-6alkyloxyC1-6alkyl, particularly carboxymethoxypropyl or carboxyethoxy-propyl; C1-6alkylcarbonyloxyC1-6alkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are xcex2-CD, randomly methylated xcex2-CD, 2,6-dimethyl-xcex3-CD, 2-hydroxyethyl-xcex2-CD, 2-hydroxyethyl-xcex3-CD, 2-hydroxypropyl-xcex3-CD and (2-carboxymethoxy)propyl-xcex2-CD, and in particular 2-hydroxypropyl-xcex2-CD (2-HP-xcex2-CD).
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl.
The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The M.S. value can be determined by various analytical techniques, preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10.
The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The D.S. value can be determined by various analytical techniques, preferably, as measured by mass spectrometry, the D.S. ranges from 0.125 to 3.
Due to their high degree of selectivity as IL-5 inhibitors, the compounds of formula (I) as defined above, are also useful to mark or identify receptors. To this purpose, the compounds of the present invention need to be labelled, in particular by replacing, partially or completely, one or more atoms in the molecule by their radioactive isotopes. Examples of interesting labelled compounds are those compounds having at least one halo which is a radioactive isotope of iodine, bromine or fluorine; or those compounds having at least one 11C-atom or tritium atom.
One particular group consists of those compounds of formula (I) wherein R4 and/or R5 are a radioactive halogen atom. In principle, any compound of formula (I) containing a halogen atom is prone for radiolabelling by replacing the halogen atom by a suitable isotope. Suitable halogen radioisotopes to this purpose are radioactive iodides, e.g. 122I, 123I, 125I, 131I; radioactive bromides, e.g. 75Br, 76Br, 77Br and 82Br, and radioactive fluorides, e.g. 18F. The introduction of a radioactive halogen atom can be performed by a suitable exchange reaction or by using any one of the procedures as described hereinabove to prepare halogen derivatives of formula (I).
Another interesting form of radiolabelling is by substituting a carbon atom by a 11C-atom or the substitution of a hydrogen atom by a tritium atom.
Hence, said radiolabelled compounds of formula (I) can be used in a process of specifically marking receptor sites in biological material. Said process comprises the steps of (a) radiolabelling a compound of formula (I), (b) administering this radio-labelled compound to biological material and subsequently (c) detecting the emissions from the radiolabelled compound. The term biological material is meant to comprise every kind of material which has a biological origin. More in particular this term refers to tissue samples, plasma or body fluids but also to animals, specially warm-blooded animals, or parts of animals such as organs.
The radiolabelled compounds of formula (I) are also useful as agents for screening whether a test compound has the ability to occupy or bind to a particular receptor site.
The degree to which a test compound will displace a compound of formula (I) from such a particular receptor site will show the test compound ability as either an agonist, an antagonist or a mixed agonist/antagonist of said receptor.
When used in in vivo assays, the radiolabelled compounds are administered in an appropriate composition to an animal and the location of said radiolabelled compounds is detected using imaging techniques, such as, for instance, Single Photon Emission Computerized Tomography (SPECT) or Positron Emission Tomography (PET) and the like. In this manner the distribution of the particular receptor sites throughout the body can be detected and organs containing said receptor sites can be visualised by the imaging techniques mentioned hereinabove. This process of imaging an organ by administering a radiolabelled compound of formula (I) and detecting the emissions from the radioactive compound also constitutes a part of the present invention.
In general, it is contemplated that a therapeutically effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, in particular from 0.05 mg/kg to 10 mg/kg body weight. A method of treatment may also include administering the active ingredient on a regimen of between two or four intakes per day.